CAREER: Mechanistic Studies of Tyrosine Derived Cofactors

铜胺氧化酶（CAO）和赖氨酰氧化酶（LOX）属于含有醌辅因子的蛋白质家族，所述醌辅因子分别由酪氨酸、2，4，5-三羟基-苯丙氨酸醌（TPQ）和赖氨酸酪氨酰醌（LTQ）在后处理中形成。这些酶催化生物胺的修饰，并在细胞信号传导和胶原蛋白形成中发挥作用。这些醌辅因子的结构/功能研究是必不可少的，以表征其化学性质的差异。虽然TPQ在CAO催化中的化学功能已经得到了很好的研究，但对LTQ知之甚少。此外，铜在两种酶中的催化作用仍不清楚。该研究项目将进一步确定TPQ和LTQ的化学性质以及铜在CAO催化中的作用，并开发一个模型系统来了解LTQ在LOX中的化学功能。该研究利用生物化学，分子生物学，生物无机和合成有机化学的工具和技术。这项研究的结果不仅将拓宽对醌蛋白的理解，而且将影响对自然界中广泛存在的其他交联醌的基本理解。这将有助于理解选择一个醌辅因子在其他生物system.Broader影响的进化优势：这个多学科的项目提供了一个很好的机会，研究生和本科生在化学和生物学的接口研究，并参与国际合作。将启动一个外联方案，邀请当地高中的女学生在堪萨斯大学化学系学习两周。学生们将在实验室工作，并与女教师和研究生讨论科学和妇女在化学方面面临的问题。这些经验旨在鼓励更多的妇女从事化学职业，从一开始就表明学术环境可以支持妇女。该研讨会还将表明，化学是一个多样化的主题，其范围比通常在高中教授的内容要广泛得多。与此同时，将开发一门针对高水平本科生和研究生的化学生物学课程，以展示如何使用化学方法来理解生物系统的基本方面。该课程将包括蛋白质化学，特别是翻译后修饰以及前沿发现的调查，旨在向学生展示化学家可以在生物科学的前沿做出重要贡献。参加堪萨斯大学少数民族学生发展倡议（IMSD）-生物科学倡议计划的学生将被鼓励参加本课程。主要研究者将通过该计划积极招募少数民族本科生进入她的实验室，以帮助他们在化学生物学领域进行研究生学习和研究生涯。

Copper amine oxidase (CAO) and lysyl oxidase (LOX) belong to a family of proteins that contain quinone cofactors that are formed post-translationally from tyrosine, 2,4,5-trihydroxy-phenylalanine quinone (TPQ), and lysine tyrosylquinone (LTQ), respectively. These enzymes catalyze the modification of biogenic amines and play roles in cell signaling and collagen formation. The structure/function study of these quinone cofactors is essential to characterize the differences in their chemical properties. Although the chemical function of TPQ in CAO catalysis has been well studied, very little is known about LTQ. Further, the role of copper in catalysis in both enzymes remains unclear. The research project will further define the chemical properties of TPQ and LTQ and the role of copper in CAO catalysis, as well as develop a model system to understand the chemical function of LTQ in LOX. The research utilizes the tools and techniques of biochemistry, molecular biology, bioinorganic and synthetic organic chemistry. The results of this research will not only broaden understanding of quinoproteins but also impact fundamental understanding of other cross-linked quinones that are widely found in nature. This will aid in understanding the evolutionary advantage of selecting one quinone cofactor over the other in biological systems.Broader Impact: This multidisciplinary project provides an excellent opportunity for graduate and undergraduate students to study at the interface of chemistry and biology and participate in an international collaboration. An outreach program will be initiated to invite female students from local high schools to spend two weeks in the Chemistry department at the University of Kansas. The students will work in the laboratory and meet with female faculty and graduate students to discuss both science and the issues facing women in chemistry. These experiences are intended to encourage more women to follow careers in chemistry by demonstrating at the outset that the academic environment can be supportive to women. The workshop will also show that chemistry is a diverse subject that is much broader in scope than what would typically be taught in high school. In concert, a chemical biology course targeting upper level undergraduate and graduate students will be developed to demonstrate how chemical methods are used to understand fundamental aspects of biological systems. The course will include protein chemistry, especially post-translational modifications as well as a survey of cutting edge discoveries, intended to show students that chemists can make important contributions at the cutting-edge of biological science. Students participating in the Initiative for Minority Student Development (IMSD)-Bioscience Initiative program at the University of Kansas will be encouraged to enroll in this course. The principal investigator will actively recruit minority undergraduate students through this program into her laboratory to help them in pursuing graduate studies and a research career in the field of chemical biology.